This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Liver has a remarkable capacity to regenerate following partial hepatectomy (PHX) or drug-induced liver injury. Regeneration of liver is characterized by the precise control of organ size at the end of regeneration resulting in re-growth of liver precisely to the pre-hepatectomy size. The mechanisms regulating termination of liver regeneration and organ size control prohibiting uncontrolled liver growth are unclear. The goal of the proposed studies is to investigate the role of Hepatocyte Nuclear Factor-4a (HNF-4a, NR2A1) in termination of liver regeneration. The central hypothesis is that, HNF4a, a master regulator of hepatocyte differentiation is involved in termination of liver regeneration by inhibiting cell proliferation and inducing hepatocyte differentiation. Recent studies have also demonstrated that HNF-4a, in addition to regulating hepatic differentiation, can also regulate cell cycle inhibitors, such as p21/WAF1. The role of HNF-4a in termination of liver regeneration after PHX will be studied using liver specific HNF-4a knockout mice, HNF-4a knockdown in wild type mice using morpholino antisense oligos, as well as following over expression of HNF-4a by in vivo gene delivery prior to PHX. Further, we will investigate whether HNF-4a can control expression of key cell cycle regulators during termination of liver regeneration after partial hepatectomy. The results of this study will not only shed light on crucial cell cycle and organ size regulation mechanisms in the liver, but will also open novel targets for intervention during uncontrolled liver growth as observed in liver cancers.